Resolved
Authors: Martha Pavlakis
Journal: Journal of the American Society of Nephrology (2007)

At first glance, debating in favor of calcineurin inhibitor withdrawal over steroid withdrawal appears to be a fool's task. In 2005, 26% of kidney transplant recipients were discharged on steroid-free regimens; the vast majority were on calcineurin inhibitor–based regimens, whereas <5% are discharged on calcineurin inhibitor–free regimens.1 Thus, the transplant community has already spoken; a steroid-free regimen is more acceptable to kidney transplant programs than calcineurin inhibitor–free immunosuppression. Most kidney transplant recipients are still discharged from their initial hospitalization on both steroids and calcineurin inhibitors, so it is safe to say that the majority of programs are not practicing early withdrawal of either agent. But a second look at this debate begs the following question. When long-term graft failure is still a major obstacle in kidney transplantation, why would we chronically prescribe nephrotoxic agents known to cause allograft loss over a preference for steroid withdrawal, when we now have so many immunosuppression choices? Are the beneficial immunosuppressive effects of calcineurin inhibitors really irreplaceable? In this debate, I would like to briefly review long-term use of steroids and calcineurin inhibitors, outcome data for steroid or calcineurin inhibitor elimination, and toxicity associated with continuation of either of these agents. In the early years of successful kidney transplantation, the use of high doses of steroids for prevention and treatment of acute rejection led many to view steroids as the main target for elimination, given their well-known side effects. The introduction of calcineurin inhibitors and, subsequently, mycophenolate mofetil, and more reliable forms of antibody induction therapy has led to several phenomena. First, the incidence of acute rejection from 1996 to 2003 has decreased from 51% to 13%.1 Second, there are now a variety of immunosuppressive agents that can be used safely and successfully. Finally, kidney transplant programs are using steroid therapy much less frequently, whether or not they practice steroid withdrawal. Although the incidence of early rejection and overall steroid use have been minimized, long-term graft survival remains problematic.2 The ideal maintenance regimen for immunosuppression would be one that ensures the early successful outcomes achieved in the prior two decades and resolves the persistent decline in renal function and eventual graft loss that currently limits out-year success. Although recent evidence is highly supportive of modern early steroid withdrawal, 5-yr data published to date is based on results from just 27 patients.3 The same can be said for a calcineurin inhibitor–free approach, using instead sirolimus, mycophenolate mofetil, steroids, and induction antibody therapy, where a recent 5-yr follow-up of 26 patients looks promising.4 Neither approach has adequate long-term outcomes or numbers for definitive declarations of success. Both long-term calcineurin inhibitor therapy and long-term steroid therapy are associated with complications linked to cardiovascular disease, such as new-onset diabetes, lipid disorders, and hypertension. Thus, elimination of either or both agents from immunosuppression regimens could eliminate some cardiovascular morbidity and mortality seen in long-term follow-up. Although the long-term direct effect of calcineurin inhibitors on graft function is known, it has been argued it is not necessarily universal. A small but instructive study from Australia with serial biopsies in calcineurin inhibitor-treated patients found the median onset of the first lesion of calcineurin inhibitor nephrotoxicity was 0.5 yr5 and these lesions were near universal by 10 yr.6 The histologic onset of these lesions was not statistically different when choosing tacrolimus versus cyclosporine. It has been rightly pointed out that much of the observed histologic damage, especially the arteriolar hyalinosis, could have been the result of early high calcineurin inhibitor exposure. The finding of arteriolar hyalinosis, which preceded the onset of clinical hypertension, suggests that calcineurin inhibitor toxicity, whether from early high-dose exposure or chronic lower level exposure, is damaging the allograft in a certain proportion of patients.7 Stable creatinine values in patients on long-term calcineurin inhibitors are on the surface reassuring.8 However, a sudden increase in creatinine that was previously stable for years often prompts a biopsy, which shows interstitial fibrosis and tubular atrophy that is likely long-standing. I believe we are often falsely reassured by a stable creatinine, a situation that may reflect compensatory hypertrophy, a response to renal injury in which undamaged nephrons hypertrophy to keep up with increased excretory demands.9 In addition, graft loss as a result of recipient death can serve to keep chronic allograft injury hidden from analysis. Having said this, however, I do believe there are likely multiple factors that protect some recipients from calcineurin inhibitor-mediated nephrotoxicity, just as some patients get severe tacrolimus-related neurotoxicity and others do not. Whereas not every patient on long-term calcineurin inhibitors is at risk for calcineurin inhibitor–related allograft damage, the study by Nankivell et al.6 suggests that histologic injury from calcineurin inhibitors is universal, although some patients are spared significant damage. Concerns about the toxicity of some calcineurin inhibitor–free regimens are justified. For example, sirolimus was initially tested as an adjunct to cyclosporine therapy, a combination we now know to be highly nephrotoxic and associated with worse allograft outcomes.10 Accordingly, the small numbers of patients discharged with a functioning kidney transplant on this regimen decreased between 2000 and 2004,1 with <50% of recipients still on that combination 2 yr posttransplant. Early sirolimus side effects seem to limit long-term sirolimus use more frequently than side effects of tacrolimus. Flechner's group4 showed comparable acute rejection rates and graft survival in kidney allograft recipients with calcineurin inhibitor–based immunosuppression and with mycophenolate mofetil/sirolimus immunosuppression given with induction therapy. Retrospective analysis of the data in the Scientific Registry of Transplant Recipients11 suggests worse acute rejection rates in the calcineurin inhibitor–free arms using just mycophenolate mofetil/sirolimus. Importantly, the calcineurin inhibitor–free patients in this analysis were less likely to receive induction immunosuppression, which may partly explain the results. Retrospective database analyses do not establish cause-and-effect relationships, and these results stand in contrast with those of controlled clinical trials. A recent head-to-head study of tacrolimus versus sirolimus in a steroid-maintenance protocol in which all patients received antithymocyte globulin induction therapy, showed no differences in measured GFR or rejection rates between the two groups.12 Biopsy results showed fewer chronic vascular changes in the sirolimus group as compared with the tacrolimus group. Biopsy findings were significantly worse for tacrolimus patients in both the intention to treat groups (P = 0.03) and when analyzed for patients remaining on the initial study drug. A greater percentage of patients assigned to sirolimus discontinued the drug (38%) as compared with those assigned to tacrolimus (16%). Tolerability is an important limiting factor to calcineurin inhibitor–free regimens that contain sirolimus. The premise of the debate assumes there is one right answer: Either steroids should go or calcineurin inhibitors should go. In hypertension management, approach to BP control in a patient with proteinuria is different than in the otherwise healthy 30-yr-old. Similarly, we need to redefine the debate in terms of risk stratification that we can ascertain from the time of transplantation and subsequently adjust our approach on the basis of posttransplant events and individual medication responses. Is there an optimal regimen to be applied broadly to all transplant patients? Given the variety of induction agents and maintenance regimens from which to choose, many have argued that there is no optimal immunosuppressive drug regimen, only optimal outcomes. I will make the following recommendations based not on randomized controlled data but on experience and opinion. The use of both steroids and calcineurin inhibitors need to be minimized. In our program, we try to eliminate both. In low-risk patients, we use antithymocyte globulin to allow a rapid steroid withdrawal in a setting of mycophenolate mofetil and tacrolimus. Then at 2 to 3 mo after transplantation in stable, rejection-free patients, we introduce sirolimus and taper calcineurin inhibitor. If sirolimus is tolerated, the calcineurin inhibitor is stopped. The patients are closely followed with quarterly fasting lipid profiles, urine protein to creatinine ratios with each laboratory visit, a BK screening protocol, and frequent clinic visits to ascertain the tolerability of immunosuppression. Using this approach, we have not had any rejection episodes to date in our kidney alone patients; this has not been the case in our pancreas after kidney transplant recipients, in whom we no longer attempt calcineurin inhibitor withdrawal. In kidney-alone recipients, a proportion of our patients do not tolerate sirolimus and are either restarted on low-dose calcineurin inhibitor or low-dose steroid therapy. But for those that tolerate mycophenolate mofetil and sirolimus, we think we have the best of both worlds. Patients benefit from the perioperative antiinflammatory effects of steroids with antithymocyte globulin and the early protection from acute rejection offered by antibody induction and calcineurin inhibitors. Then they are individually tested for tolerability by exposure to a maintenance immunosuppression regi-men that is free of either long-term steroid or calcineurin inhibitor effects. For the foreseeable future, transplant clinicians will continue to juggle both drug toxicities and fairly dramatic differences in individual responses to our most commonly used agents. Some patients will have an absolutely insurmountable obstacle to continuing any given therapy (near fatal hyperkalemia on tacrolimus, severe aphthous ulcerations on sirolimus, and the like). We may debate which toxic immunosuppressant is best eliminated in the long run, but it's clear that targeting improvements in long-term allograft function is a goal about which there is no debate. The development of nonnephrotoxic calcineurin inhibitors, new biologics, and signal transduction inhibitors promise even more opportunity to decrease our patients' exposure to both steroids and nephrotoxic calcineurin inhibitors. DISCLOSURES None.